Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma

Abstract

Background: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC.

Materials and methods: Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS).

Results: All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses.

Conclusion: In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

Fig 1. Representative images of immunostainings.

(A, B) Immunoreactivity for chromogranin A, (C, D) Ki67 and (E, F) p53. The left panel demonstrates staining of a pancreatic primary tumor. The right panel shows the respective staining from a rectal primary tumor. Scale bar = 100 μm.

Fig 2. Immunohistochemical images of scattered and dense staining pattern.

Scattered and dense staining pattern for two p53 immunoreactive tumors. (A) Scattered type. Single immunoreactive cells spread out in the whole tumor sample. (B) Dense type. Widespread immunoreactivity of the entire tumor specimen. (C) and (D) represent Ki67 for each tumor respectively. Scale bar = 100 μm.

Fig 3. Kaplan-Meier curves.

Kaplan-Meier survival curves for GEP-NECs divided according to primary tumor origin and p53 immunoreactivity. (A) Progression-free survival (PFS) for the complete cohort of 124 patients, p = 0.97. (B) Overall survival (OS) for the complete cohort of 124 patients, p = 0.54. (C) PFS for colorectal patients p = 0.03 (D) and (E) PFS and OS for colorectal patients with distant metastases, p = 0.01 and p = 0.02 respectively.